The objective of the proposed research program is to find ways of protecting insulin from degradation by proteolytic digestion when given orally. The program is geared to utilize liposomes as carriers to mediate the uptake of the hormone through the gastrointestinal tract. The focus of the research is on the application of a new physical technique, gamma-ray perturbed angular correlation (PAC), and other biochemical methods for investigating factors that might enhance the uptake of the encapsulated insulin by gastrointestinal tract, so that the hormone retains its therapeutic value after being absorbed in the circulation. This research will be directed to two specific areas, namely, the mechanisms of protection and absorption of insulin in liposomes. To investigate the mechanism of protection, the effectiveness of the liposome-encapsulated insulin in lowering the blood-glucose levels of diabetic and normal animals will be studied as a function of the physical properties of liposomes, primarily the in vitro and in vivo permeability of liposomes. The entrance into circulation of liposome-encapsulated insulin could be via intact liposomes, or via reorganized lipid-insulin complexes, or via a combination of both mechanisms. To resolve these possible mechanisms, three different approaches will be tried. These are: (1) the investigation of percentage of intact liposomes in the circulation by the PAC technique; (2) the application of radioimmunoassay to measure the amount of exogenous insulin which is protected by lipids; and (3) the use of two-phase chloroform-aqueous buffer system to investigate the presence of insulin-phospholipid complex in the serum.